NNI seeks to ameliorate neurodegeneration seen in Alzheimer's disease and other dementias. Toward this end, NNI scientists have targeted neurofibrillary tangle (NFT) formation for drug discovery. These lesions appear in concert with the onset of memory loss in AD, and are in fact the best markers for AD neurodegeneration known in the scientific literature. Thus NNI has pursued agents that interfere with NFT formation. As part of Phase I effort, the feasibility of inhibiting tau filament formation and driving filament depolymerization in vitro using small, drug-like ligands was demonstrated. Moreover, the ability of one such molecule to halt progression of neurodegeneration in an animal model of disease was shown. The goal of Phase II effort is to extend these results by validating tau fibrillization as a drug target, and proving that in vitro screening technology can successfully identify compounds that are active in animal models of tau-induced neurodegeneration. There are three Aims. First, NNI will expand its screening effort to identify additional classes of molecules with anti tau polymerization activity. NNI has shown the feasibility of using its screening technology to identify such molecules. Second, NNI will characterize the mechanism of action of its compounds, establishing a structure activity relationship for members of the existing structural family. Finally, NNI will examine the activity of active compounds in vivo, demonstrating entry into the brain, and determining a structure activity relationship for in vivo activity. At the end of the project, NNI will be in position to establish neuritic lesions (e.g., NFTs) as an authentic target for intensive preclinical development.